The present invention relates to cyclodextrin complexes, and more particularly relates to a highly water soluble derivitized beta cyclodextrin complex which contains significant amounts of salicylic acid (SA).
Cyclodextrins are a class of cavity-containing cyclic compounds (oligosaccharides), sometimes described as being donut-shaped, which possess a property of forming special type complexes known as molecular inclusion complexes. Molecular inclusion complexes are molecular compounds which display a characteristic structure of an adduct, that is, they are constructed such that one component (the host) spatially encloses another (the guest), as shown in FIG. 1A. There, an anchored or entrapped guest 1 is typically an active agent, such as a chemical compound, disposed within a cavity 3' of the cyclodextrin molecule 3. The guest's entrapment within the cyclodextrin (complexing agent or host) defines a complex relationship which is devoid of covalent bonds.
The resulting complex may render light and/or oxygen-sensitive material more stable, as well as biologically active substances more controllable. That is, the properties of the host:guest complex may be quite different than those of the host or guest individually. For example, the overall water solubility of the guest may be enhanced relative its water solubility in the uncomplexed state.
Cyclodextrins are synthesized from starch hydrolyzates utilizing transglycosidases. The resulting molecular structure of the cyclodextrins may include from six (6), seven (7), or eight (8) glucopyranose rings, respectively known as ALPHA, BETA, and GAMMA cyclodextrins. An ALPHA cyclodextrin 4 is shown in FIG. 2. Cyclodextrins are water-soluble, a property derived from the location of free hydroxyl groups of each successive glucose unit on "rims" or edges of the donut-shaped cyclodextrin molecules.
FIG. 1B highlights the position of the primary hydroxyl groups, which are located at the outer surface 4 of the ring of cyclodextrin structure 2. The secondary hydroxy groups are located on the opposite edge 6 of the structure. The outer structural portion of the cyclodextrin molecule is substantially hydrophilic, whereas its inner cavity is strongly hydrophobic. Strongly hydrophilic molecules, and strongly hydrated and ionized groups are not, or are only weakly, complexable. Only molecules which are relatively hydrophobic in nature are readily complexable. It follows that the stability of a complex formed is substantially proportional to the hydrophobic character of the guest molecule or moiety, and, concomitantly, well complexable guests are typically poorly soluble in water.
The guest (guests, or portions thereof, depending on the stoichiometry of the complex) is held via non-covalent forces in a form of three distinct spatial bands (or relationships) within the cyclodextrin/active agent complex structure. There are two bands of C--H groups and a band of glycosidic oxygens. The bands form a cooperative array of binding sites which together comprise a relatively non-polar lipophilic micro-environment. Binding facilitated thereby is not fixed or permanent. It is governed by an inherent dynamic equilibrium which is itself dependent upon the geometric and spatial fit of the host/guest molecules, and the solubility of the guest in the medium.
The term, complex stability, refers to a dissociation/association equilibrium of host and guest in solution. Forces (associative/dissociative) interact simultaneously to maintain the complex in its complexed state. Several examples are: hydrophobic interaction forces, Van der Waal forces, London dispersion forces, hydrogen bonding forces, the release of high energy water upon guest inclusion (complexing) and release of conformational strain in a cyclodextrin water adduct.
Complexation can occur either in solution or in the solid state. Heating the solution and/or solid state mixture increases cyclodextrin solubility as well as that of the guest. Those cases in which the guest includes a charged group extending out of the cavity after complexation tend to form soluble complexes. Because different guests typically display varying degrees of solubility in water, and complexation is dependent upon the amount of guests coming into contact with host molecules, organic solvents are sometimes needed to sufficiently dissolve the guest, for example, methanol, ethanol, propanol, etc.
Chemically modified cyclodextrins display physicochemical and inclusion behavior properties which differ from those of unmodified cyclodextrins. Modifying cyclodextrin by adding hydroxy alkyl groups, for example, hydroxypropyl beta cyclodextrin, tends to increase solubility in water to about 60 % or more, which cannot be realized using the unmodified cyclodextrins. FIG. 2 shows the chemical structure of beta (.beta.) cyclodextrins (to be discussed in greater detail below). Similarly, other modified cyclodextrins, such as; quaternary ammonium cyclodextrin, succinylated cyclodextrin, and sulfates cyclodextrin, among others are highly water soluble. These materials are commercially available from American Maize-Products Company, Hammond, Ill.